# ROS1-positive non-small-cell lung cancer

Source: https://onco.cc/cancers/ros1-positive-nsclc/  
OnCo record `ros1-positive-nsclc` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

ROS1-positive lung cancer is a rare fusion-driven adenocarcinoma treated with a pill. Crizotinib was the first, and the newer drugs repotrectinib and taletrectinib control the disease for about three years, reach the brain and work against the resistance mutation that defeated the older drugs.

## Summary

ROS1 fusions were identified in lung cancer in 2007 alongside ALK, and because the two kinases are closely related the ALK inhibitor crizotinib also blocked ROS1. In the ROS1 cohort of PROFILE 1001 the response rate was 72 percent and median progression-free survival 19.2 months, and crizotinib was approved for ROS1-positive lung cancer in March 2016 on that single-arm evidence. Its weaknesses were poor brain penetration and resistance through the G2032R solvent-front mutation.

Entrectinib, a ROS1, NTRK and ALK inhibitor with brain penetration, was approved in August 2019 on an integrated analysis of its phase 1 and 2 studies (STARTRK-2 among them) with a response rate of 77 percent and intracranial responses. Repotrectinib, a compact macrocycle designed to fit around solvent-front mutations, was approved in November 2023 on TRIDENT-1: a 79 percent response rate and median progression-free survival of 35.7 months in inhibitor-naive patients, and a 38 percent response rate after one prior inhibitor, including G2032R disease. Taletrectinib, tested in the TRUST-I and TRUST-II studies, was approved in June 2025 with high response rates in both inhibitor-naive and crizotinib-pretreated patients and less dizziness than repotrectinib.

Zidesamtinib (NVL-520) is designed to spare TRK and so avoid the dizziness and weight gain of the current drugs. Chemotherapy with platinum-pemetrexed remains effective once inhibitors are exhausted, and checkpoint inhibitors add little. Open questions are the best first drug now that three brain-penetrant inhibitors exist and how to treat bypass resistance through MET or KRAS.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: ROS1-rearranged lung cancer; ROS1 fusion NSCLC; CD74-ROS1 lung cancer
- Tags: subtype-page; lung
- Group: lung
- Burden: About 1 to 2 percent of non-small-cell lung cancers carry a ROS1 fusion, typically adenocarcinoma in younger patients who have never smoked; about a third have brain metastases at some point.
- Subtypes: ROS1 fusion adenocarcinoma, inhibitor-naive (repotrectinib, taletrectinib, entrectinib or crizotinib); ROS1-positive disease with brain metastases at diagnosis; Crizotinib-resistant ROS1 disease (G2032R solvent-front mutation; repotrectinib, taletrectinib); Bypass resistance through MET or KRAS after ROS1 inhibitors
- Biomarkers: ROS1 fusion by RNA sequencing, fluorescence in situ hybridisation or immunohistochemistry with confirmation; ROS1 resistance mutations at progression (G2032R, D2033N, L2026M); Brain MRI at diagnosis and during follow-up; Bypass alterations (MET amplification, KRAS) at progression

## Standard of care

- Advanced, first line: Repotrectinib (TRIDENT-1) or taletrectinib as preferred; entrectinib or crizotinib as alternatives, entrectinib when brain metastases are present. ([Repotrectinib](https://onco.cc/drugs/repotrectinib/), [A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements](https://onco.cc/trials/nct03093116/), [Taletrectinib](https://onco.cc/drugs/taletrectinib/), [A Study of AB-106 in Subjects With Advanced NSCLC Harboring ROS1 Fusion Gene](https://onco.cc/trials/nct04395677/), [Entrectinib](https://onco.cc/drugs/entrectinib/), [Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangeme](https://onco.cc/trials/nct02568267/), [Crizotinib](https://onco.cc/drugs/crizotinib/), [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/))
- Advanced, after crizotinib or entrectinib: Repotrectinib or taletrectinib, which cover G2032R; zidesamtinib in trials; platinum-pemetrexed once inhibitors are exhausted. ([Repotrectinib](https://onco.cc/drugs/repotrectinib/), [Taletrectinib](https://onco.cc/drugs/taletrectinib/), [Zidesamtinib](https://onco.cc/drugs/zidesamtinib/), [On-target resistance mutations (gatekeeper, solvent-front, compound)](https://onco.cc/terms/gatekeeper-mutation/), [Pemetrexed](https://onco.cc/drugs/pemetrexed/), [Carboplatin](https://onco.cc/drugs/carboplatin/))
- Brain metastases: Brain-penetrant inhibitors (repotrectinib, taletrectinib, entrectinib) with stereotactic radiosurgery for large or symptomatic lesions. ([Repotrectinib](https://onco.cc/drugs/repotrectinib/), [Entrectinib](https://onco.cc/drugs/entrectinib/), [Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)](https://onco.cc/technologies/radiosurgery-srs/), [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/))

## State of the art

- Repotrectinib and taletrectinib give about three years of control first line and cover the G2032R mutation.
- Three brain-penetrant inhibitors approved between 2019 and 2025 after crizotinib's decade alone.
- Zidesamtinib designed to spare TRK and remove the dizziness and weight gain of dual ROS1/TRK inhibitors.

## Open problems

- No randomised trial compares the ROS1 inhibitors; choice rests on single-arm response rates and side-effect profiles.
- Dizziness, weight gain and paraesthesia from TRK inhibition limit the current brain-penetrant drugs.
- Resistance through MET, KRAS and other bypass routes has no approved targeted option.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/ROS1
- Wikipedia: https://en.wikipedia.org/wiki/ROS1
- NCCN Guidelines: Non-Small Cell Lung Cancer: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450

## Connected records

- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/), [Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)](https://onco.cc/technologies/radiosurgery-srs/)
- targets: [MET](https://onco.cc/targets/met/), [NTRK](https://onco.cc/targets/ntrk/), [ROS1](https://onco.cc/targets/ros1/)
- drugs: [Carboplatin](https://onco.cc/drugs/carboplatin/), [Crizotinib](https://onco.cc/drugs/crizotinib/), [Entrectinib](https://onco.cc/drugs/entrectinib/), [Pemetrexed](https://onco.cc/drugs/pemetrexed/), [Repotrectinib](https://onco.cc/drugs/repotrectinib/), [Taletrectinib](https://onco.cc/drugs/taletrectinib/), [Zidesamtinib](https://onco.cc/drugs/zidesamtinib/)
- companies: [Bristol Myers Squibb](https://onco.cc/companies/bms/), [Nuvalent](https://onco.cc/companies/nuvalent/), [Nuvation Bio](https://onco.cc/companies/nuvation-bio/), [Pfizer (incl. Seagen)](https://onco.cc/companies/pfizer/), [Roche / Genentech](https://onco.cc/companies/roche-genentech/)
- pathways: [Non-small cell lung cancer (KEGG map)](https://onco.cc/pathways/nsclc-signalling/), [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/)
- terms: [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/), [Gene fusion](https://onco.cc/terms/gene-fusion/), [On-target resistance mutations (gatekeeper, solvent-front, compound)](https://onco.cc/terms/gatekeeper-mutation/), [Oncogene addiction](https://onco.cc/terms/oncogene-addiction/), [Tyrosine kinase inhibitor (TKI)](https://onco.cc/terms/tki-term/)
- trials: [A Phase III Study Comparing Taletrectinib With Standard Therapy in ROS1 Positive Locally Advanced or Metastatic Non-small Cell Lung Cancer Patients](https://onco.cc/trials/nct06564324/), [A Study of AB-106 in Subjects With Advanced NSCLC Harboring ROS1 Fusion Gene](https://onco.cc/trials/nct04395677/), [A Study of Lorlatinib in Subjects With ROS1-Positive Non-Small Cell Lung Cancer](https://onco.cc/trials/nct05297890/), [A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements](https://onco.cc/trials/nct03093116/), [A Study of Repotrectinib Versus Crizotinib in Participants With Locally Advanced or Metastatic Tyrosine Kinase Inhibitor (TKI)-naïve ROS1-positive Non-Small Cell Lung Cancer (NSCLC) (TRIDENT-3)](https://onco.cc/trials/nct06140836/), [A Study of XZP-5955 Tablets in Patients With NTRK or ROS1 Fusion Positive Locally Advanced or Metastatic Solid Tumors](https://onco.cc/trials/nct04996121/), [A Study to Compare the Efficacy and Safety of Entrectinib and Crizotinib in Participants With Advanced or Metastatic ROS1 Non-small Cell Lung Cancer (NSCLC) With and Without Central Nervous System (CNS) Metastases](https://onco.cc/trials/nct04603807/), [Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangeme](https://onco.cc/trials/nct02568267/), [Phase 3 Study of Taletrectinib vs Placebo as an Adjuvant Therapy in ROS1 Positive NSCLC (TRUST-IV)](https://onco.cc/trials/nct07154706/), [Taletrectinib Phase 2 Global Study in ROS1 Positive NSCLC](https://onco.cc/trials/nct04919811/)
- people: [Alexander Drilon](https://onco.cc/people/alexander-drilon/), [Byoung Chul Cho](https://onco.cc/people/cho-byoung-chul/), [D. Ross Camidge](https://onco.cc/people/ross-camidge/)
- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)

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JSON: https://onco.cc/api/v1/entities/ros1-positive-nsclc.json